Genotype- and Phenotype-Based Subgroups in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The EYE-RISK Consortium.

PURPOSE: Geographic atrophy (GA) secondary to age-related macular degeneration is considered a single entity. This study aimed to determine whether GA subgroups exist that can be defined by their genotype and phenotype. DESIGN: Retrospective analysis of cross-sectional data. PARTICIPANTS: Individuals (196 eyes of 196 patients) 50 years of age or older with GA from the EYE-RISK database. METHODS: Participants were graded for the presence of each of the following fundus features on color fundus photography: large soft drusen, reticular pseudodrusen (RPD), refractile drusen, hyperpigmentation, location of atrophy (foveal vs. extrafoveal), and multifocal lesions. Genotypes of 33 single nucleotide polymorphisms previously assigned to the complement, lipid metabolism, or extracellular matrix (ECM) pathways and ARMS2 also were included, and genetic risk scores (GRSs) for each of those 3 pathways were calculated. Hierarchical cluster analysis was used to determine subgroups of participants defined by these features. The discriminative ability of genotype, phenotype, or both for each subgroup was determined with 10-fold cross-validated areas under the receiver operating characteristic curve (cvAUCs), and the agreement between predicted and actual subgroup membership was assessed with calibration plots. MAIN OUTCOME MEASURES: Identification and characterization of GA subgroups based on their phenotype and genotype. RESULTS: Cluster analyses identified 3 subgroups of GA. Subgroup 1 was characterized by high complement GRS, frequently associated with large soft drusen and foveal atrophy; subgroup 2 generally showed low GRS, foveal atrophy, and few drusen (any type); and subgroup 3 showed a high ARMS2 and ECM GRS, RPD, and extrafoveal atrophy. A high discriminative ability existed between subgroups for the genotype (cvAUC, ≥0.94), and a modest discriminative ability existed for the phenotype (cvAUC, <0.65), with good calibration. CONCLUSIONS: We identified 3 GA subgroups that differed mostly by their genotype. Atrophy location and drusen type were the most relevant phenotypic features.

Longitudinal changes in outer nuclear layer thickness in soft drusen and reticular pseudodrusen.

BACKGROUND: Drusen are seen in the early and intermediate stages of age-related macular degeneration. A retrospective, two-year observational study at a tertiary centre was designed to assess outer nuclear layer thickness in different types of drusen. METHODS: Patients over 50 years of age with predominant soft drusen or reticular pseudodrusen were included in the study. Fundus photography, infrared, fundus autofluorescence and spectral domain optical coherence tomography were performed at baseline, years one and two. Outer nuclear layer thickness was measured in the nine Early Treatment Diabetic Retinopathy Study subfields, and the rate of thinning was determined using generalised estimating equations models. RESULTS: Data were analysed from 17 eyes with soft drusen and nine eyes with reticular pseudodrusen. Greater outer nuclear layer thinning was seen overall and in all subfields in reticular pseudodrusen as compared to soft drusen, with statistically significant differences found mostly in superior and nasal subfields of ring 2. The outer nuclear layer was 5-12 µm thinner in eyes with reticular pseudodrusen, and the rate of thinning was greater in eyes with reticular pseudodrusen in the outer superior subfield. CONCLUSIONS: Outer nuclear layer thickness is consistently lower in patients with reticular pseudodrusen compared with soft drusen, irrespective of subfield location. These structural findings may contribute to explain the functional abnormalities observed in patients with reticular pseudodrusen.